Targeting the HER2 network: what’s new? P Pronzato, Genova.

Targeting the HER2 network:what’s new?

P Pronzato, Genova

2

HER2 Overexpression Leads to Increased Signaling

• Increased cell proliferation• Increased cell migration• Resistance to apoptosis

Yarden et al. Nat Rev Mol Cell Biol 2001

HER2 testing

• In a randomized trial, benefit confined to HER2/neu amplified/overexpressors (Seidman, CALGB 9840)

• Subset analysis of CALGB 9840 suggests benefit in FISH-negative patients with Chr 17 2.2 (polysomy) (Kaufman, ASCO 2007)

Trastuzumab and HER2 Status in Advanced Breast Cancer:

Prior Observations

R Livingston, ASCO 2008

Kaplan-Meier Estimates of PFS: HER2-Negative Subjects

Time, weeks

Cu

mu

lati

ve p

rog

ress

ion

-fre

e su

rviv

al

0 20 40 60 80 100 120

0

0.2

0.4

0.6

0.8

1.0Polysomy 17 ≤ 2.2, L+P (n = 178)

Polysomy 17 > 2.2, L+P (n = 23)

Polysomy 17 ≤ 2.2, P (n = 183)

Polysomy 17 > 2.2, P (n = 21)

Discordance

Benefit from adjuvant trastuzumab may not be confined to patients with IHC3+ and/or FISH

positive tumors

Paik et. Al, ASCO 2007, abstr. 511

Central HER2

FISH neg.

Central IHCneg. (0-2+)

Both Negative

Before

amendment (any lab)103/529 (19.5%) 122/528 (23.1%) 87/529 (16.4%)

After amendment

(qualified lab for IHC)104/1266 (8.2%) 177/1259 (14.1%) 87/1266 (6.8%)

Total 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)


positive tumors


Central HER2

FISH neg.


Both Negative

Before


After amendment


Total 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)


positive tumors


Central HER2

FISH neg.


Both Negative

Before


After amendment


Total 207/1795 (11.5%) 299/1787 (16.7%) 174/1795 (9.7%)

Discordance primary/relapse

ECD

JC Thery

RANDOMIZATION

Paclitaxel 175 mg/m2 q3wLapatinib 1,500 mg PO QD

(N = 291)

Paclitaxel 175 mg/m2 q3w Placebo PO QD

(N = 288)

Stratification

• Disease sites

• Stage of disease

Key Inclusion

• Incurable stage III/IV

• No prior treatment for M+

• HER2-negative or untested

EGF30001 Study Design

Endpoints• Primary: TTP• Secondary: PFS, OS, safety

N = 579

Serum ECD measured by ELISA (Oncogene Science) pretreatment, week 9, and q12 weeks.

Di Leo et al. J Clin Oncol. 2008. In press.

Baseline ECD

HE

R2

IHC

5 10 50 100 5000.

00.

51.

01.

52.

02.

53.

0

Poor Correlation of Baseline ECD With HER2 Status by FISH or IHC

Correlation with IHC3+ 47/64 = 73% *FISH+: R = 0.34 (P = 0.003; n = 75) FISH–: R = 0.03 (P = 0.596; n = 327)

Baseline ECD

FIS

H R

atio

5 10 50 100 500

15

10

R = 0.28 overall (P < 0.001;n = 402)*

R = 0.34 (P< 0.001; n = 461)

Conversion From ECD-negative to -positive Is Associated With Worse PFS in HER2-negative Patients

Converting

Non-converting

(remain negative)

P + Lapatinib

Converting(n = 20)

Non-Converting

(n = 92)

Median, weeks 22.4 32.1

HR (95% CI) 2.40 (1.34 , 4.31)

P-value 0.003

Converting(n = 7)

Non-Converting

(n = 111)


HR (95% CI) 2.78 (1.27 , 6.10)

P-value 0.011

Converting

Non-converting

(remain negative)

P + Placebo

HR = Hazard of converting.

Time, weeks

PF

S

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

1.0

Time, weeks

PF

S

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

1.0

30 patients seroconvertered: 17 PR, 12 SD, 1 PD

Conversion From ECD-positive to -negative Is Associated With Improved PFS

Converting(n = 11)

Non-Converting

(n = 20)


HR (95% CI) 0.20 (0.07, 0.55)

P-value 0.002

ConvertingNon-converting

(remain positive)

P + Lapatinib

Converting(n = 19)

Non-Converting

(n = 23)


HR (95% CI) 0.50 (0.26 , 0.97)

P-value 0.040

ConvertingNon-converting

(remain positive)

P + Placebo

HR = Hazard of converting.

Time, weeks

PF

S

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

1.0

Time, weeks

PF

S

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

1.0

Trastuzumab for metastatic breast cancer

Study Design

arm A: trastuzumab (T) + docetaxel (D) (100mg/m2, q3wks),

with continuation of T after D until PD

R

arm B: trastuzumab docetaxel (100mg/m2, q3wks)

at PD

• loading dose trastuzumab 4 mg/kg, thereafter weekly 2 mg/kg

• docetaxel: at least 6 cycles

• no routine use of haematological growth factor support

Best Overall Response during treatment (RECIST criteria)

CR 7 13.5% 1 2.2 %

PR 31 59.6% 21 47.7 %

SD 6 11.5 % 15 34.1 %

PD 4 7.7 % 5 11.4 %

NE 4 7.7 % 2 4.6 %

p = 0.03

Combination Sequential

T + D T H

Median time to first progression0.

000.

250.

500.

751.

00

0 6 12 18 24 30 36analysis time

treat = A=H+T treat = B=H->T

months

time to progression 1

Monotherapy T : 3.9 mo

Combination therapyT + D: 9.4 mo

p=0.0001

Progression Free SurvivalCombination versus Sequential therapy

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36analysis time


months

time to progression

Combination T + D:9.4 mo

Sequential T D: 10.8 mo

p=0.42

Overall Survival0.

000.

250.

500.

751.

00

0 6 12 18 24 30 36analysis time


months

Hertaxsurvival

Combination T + D:30.5 mo

Sequential T D: 20.2 mo

p=0.15

Herceptin prolongs survival in women with 1st-line MBC

0 10 20 30 40 50

PH

PCarboH

DH

DCarboH

DH

D alone

PH

P alone

Median survival (months)

IHC, immunohistochemistry; P, paclitaxel

H, Herceptin; D, docetaxel; Carbo, carboplatin

H0648g(IHC 3+)

M77001

BCIRG 007

US Oncology(IHC 3+)

Smith et al 2001; Marty et al 2005 Robert et al 2006; Pegram et al 2007

CHAT: a large randomised phase II trial

No prior Herceptin, docetaxel or

Xeloda

Stratification: - prior paclitaxel

- prior anthracycline- liver metastases

- KPS

KPS = Karnofsky performance status

Wardley A et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S33(Abst 309)

HTHerceptin 8mg/kg (loading dose), d1 followed by 6mg/kg, d1, q21dDocetaxel 100mg/m2, d1

HTXHerceptin 8mg/kg (loading dose), d1followed by 6mg/kg, d1, q21dDocetaxel 75mg/m2, d1Xeloda 950mg/m2 bid, d1–14

RANDOMISATION

HTX significantly increases progression-free survival

1.0

0.8

0.6

0.4

0.2

0

Esti

mate

d p

rob

ab

ilit

y

0 5 10 15 20 25 30 35 40 45 50

Months

Events HR 95% CI p-value

HTX 75 0.725 0.529, 0.99 0.0402HT 85

Wardley A et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S33(Abst 309)

12.8 17.9

38

Phase III Study to Test if Total HER2 Blockade Improves Clinical Outcome

RANDOMIZATION

Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV qw N=148

Lapatinib 1500 mg/day PO N=148

Stratification Factors

• Visceral Disease

• Hormone Receptor

Key Inclusion

• HER2+(FISH+/ IHC3+) MBC

• Progression on• Anthracycline

• Taxane

• Trastuzumab

• Progression on most recent trastuzumab regimen

Crossover if PD after 4wk therapy (N=73)

Study conducted and funded by GlaxoSmithKline

J O Shaughnessy, ASCO 2008

39

Treatment Efficacy

*Confirmed CR+PR †CR+PR+SD ≥ 6 mo

L

N=145L + T

N=146

Response Rate, %*

(95% CI)

6.9

(3.4, 12.3)

10.3

(5.9, 16.4)

Odds Ratio (95% CI) 1.5 (0.6, 3.9)

p=0.46

Clinical Benefit Rate, %†

(95% CI)

12.4

(7.5, 18.9)

24.7

(17.9, 32.5)

Odds Ratio (95% CI) 2.2 (1.2, 4.5)

p=0.01

40

Progression-Free SurvivalL

N = 145L+T

N = 146

Progressed or Died, n 128 127

Median, wks 8.1 12.0

Hazard ratio (95% CI) 0.73 (0.57, 0.93)

P value 0.008

6 Mo PFS

Cu

mu

lati

ve %

Ali

ve w

ith

ou

t P

rog

ress

ion

Subjects At Risk148148

LL+T

5373

2142

1327

58

02

13%

28%

0

20

40

60

80

100

0 10 20 30 40 50 60Time from Randomization (wks)

Adjuvant Trastuzumab

Adjuvant Herceptin has an extensive evidence base with >13,000 patients treated in 4 major trials

Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006

NCCTG N9831 (USA)

HERA (ex-USA) BCIRG 006 (global)

NSABP B-31 (USA)

IHC / FISH

(n=5,090)

Observation1 year

2 years

IHC / FISH

(n=3,505)

1 year

1 year

FISH(n=3,222)

1 year

1 year

IHC / FISH

(n=2,030)

1 year

Docetaxel

Docetaxel + carboplatin

Doxorubicin + cyclophosphamide

Herceptin

Standard CTx

PaclitaxelIHC, immunohistochemistry

FISH, fluorescence in situ hybridisation CTx, chemotherapy

HERA

HERA updateLancet 2007

Trastuzumab sequenziale

Trastuzumab Adjuvant Trials

0 2In favor of T

HR

0.64

0.87

0.48

0.61

0.42

0.86

Study FU yrs Pts

HERA 2 3401

N9831 (arm B) 1.5 1965

Joint analysis 4 3968

BCIRG 006 3 3222

FinHER 3 231

PACS 04 4 528

1In favor of Obs.



NCCTG N9831 (USA)


NSABP B-31 (USA)

IHC / FISH

(n=5,090)

Observation1 year

2 years

IHC / FISH

(n=3,505)

1 year

1 year

FISH(n=3,222)

1 year

1 year

IHC / FISH

(n=2,030)

1 year

Docetaxel



Herceptin

Standard CTx





NCCTG N9831 (USA)


NSABP B-31 (USA)

IHC / FISH

(n=5,090)

Observation1 year

2 years

IHC / FISH

(n=3,505)

1 year

1 year

FISH(n=3,222)

1 year

1 year

IHC / FISH

(n=2,030)

1 year

Docetaxel



Herceptin

Standard CTx



Trastuzumab Adjuvant Trials

0 2In favor of T

HR

0.64

0.87

0.48

0.61

0.42

0.86

Study FU yrs Pts

HERA 2 3401

N9831 (arm B) 1.5 1965

Joint analysis 4 3968

BCIRG 006 3 3222

FinHER 3 231

PACS 04 4 528

1In favor of Obs.

Neoadjuvant Trastuzumab

Trastuzumab resistance

Lapatinib and newer drugs

72

EGF 100151 - Design

Open-label Phase III studyTyverb + Capecitabine versus Capecitabine

RANDOMIZE

N = 528 (planned total)

Tyverb 1250 mg po/day continuous + Capecitabine (2000mg/m2/day, po days 1-14 every 21 days)

Capecitabine (2500mg/m2/day, po days 1-14 every 21 days)

Adv/Met Breast Ca Prior taxanes,

anthracyclines, trastuzumab

HER2 (ErbB2)Overexpression(IHC 3+, or 2+ and FISH+)

Endpoints• Primary = Time to

Progression (TTP) by blinded independent review

• Secondary = Survival (80% power on OS), PFS, ORR

GLOBAL

EGF 100151: TTP and OS

73

D Cameron, ASCO 2007

Effect on TTP of interval between last Trastuzumab dose and random

74

Interval between last Trastuzumab dose and random

Lapatinib + Capecitabine

Capecitabine

Median TTP (weeks)

Median TTP (weeks)

< 8 weeks 27.1 18.6

> 8 weeks 26.1 14.6

p=0.004

p=0.012

Response

Lapatinib + Capecitabine (n = 198)

Capecitabine(n = 201)

Complete Response 1 (<1%) 0 (0%)

Partial Response 46 (23%) 28 (14%)

Overall Response Rate (95% CL) 23.7% (18.0-30.3) 13.9 (9.5-19.5)

75D Cameron, ASCO 2007

p = 0.017

Study DesignStudy Design

RANDOMIZATION

Paclitaxel 175 mg/m2 q3wLapatinib 1500 mg po QD

Paclitaxel 175 mg/m2 q3w Placebo po QD

Stratification

• Disease site• Disease stage

Key Inclusion

• Incurable Stage III/IV • No prior treatment for M+• HER2 negative (0, 1+, 2+

FISH-, or FISH-) or untested

39Non-MBC events, n

235213Progression, n

5.36.7Median, months

0.87 (0.72, 1.05)Hazard ratio (95% CI)

0.142P value

P + Placebo(n=288)

P + L(n=291)

Time to Progression: ITT Analysis – Time to Progression: ITT Analysis – Investigator ReviewInvestigator Review

0

10

20

30

40

50

60

70

80

90

100

0

Cu

mu

lati

ve p

rog

ress

ion

-fre

e,

%

Time, months

P + LapatinibP + Placebo

3 2118151296 24 27 30

0128192953102192288P0269233462108196291P + L

Patients at risk

Response Rate & Duration by HER2 Status Response Rate & Duration by HER2 Status

Odds ratio = 2.9 (1.1, 7.9) p = 0.027

Resp

on

se r

ate

,%

P + L P

P + L P n = 202

n = 199 n = 52 n = 39

Median duration of response*

36 (21-53)

60 (45-73)

HER2-positive HER2-negative

31 (24-38)24 (18-30)

Odds ratio = 1.5 (0.9, 2.3) p = 0.118

Median duration of response* R

esp

on

se r

ate

,%

* Based on the number of responders.

n Median, months

P + L 31 7.4

P 14 5.5

n Median, months

P + L 61 6.2

P 48 8.5

Interaction test p = 0.208 (Zelen’s homogeneity test)

P + L(n = 52)

P(n = 39)

Median, mos 8.1 5.8

HR (95% CI) 0.57 (0.34, 0.93)

P value 0.011

Time to Progression by HER2 StatusTime to Progression by HER2 Status

HER2-positive HER2-negative

Interaction test p = 0.032 (Cox’s proportional hazards model)

P + L(n = 199)

P(n = 202)

Median, mos 5.8 5.3

HR (95% CI) 1.04 (0.83, 1.30)

P value 0.747

Total 75 events (83%)

Total 299 events (75%)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30Time, months

Cu

mu

lati

ve p

rog

ress

ion

-fre

e,

%

P + Lapatinib

P + placebo

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30Time, months

P + Lapatinib

P + placebo

EGF105084: Study DesignEGF105084: Study Design

Stratification: PS and number of prior trastuzumab-containing regimens


Lapatinib Monotherapy750 mg BID


PDPD

Extension arms

Extension arms

CNS Composite Response

Best response Patients, n (%)

Complete response 0 (0)

Partial response 15 (6)

Stable disease* 102 (42)

EGF105084

* ≥ 8 weeks on study

EGF105084: Extension ArmsEGF105084: Extension Arms





PDPD

Extension arms

Extension arms

EGF105084 L + C Extension:Volumetric Reduction in Brain Metastases

n (%)

Median (range) cm3

≥ 50% Volumetric CNS tumor reductionAbsolute tumor volumetric reduction

8/40 (20)6.2 (3.2 - 12.9)

≥ 20% Volumetric CNS tumor reductionAbsolute tumor volumetric reduction

16/40 (40)3.9 (0.6 - 12.9)

EGF 100151 : Brain metastases

Lapatinib + Capecitabine(n = 198)

Capecitabine (n = 201)

Pts with symptomatic CNS progression as part of their first progression event *

4 (2%) 13 (6%)

* As assessed by independ review committee D Cameron, ASCO 2007

p = 0.045

DiarrhoeaPaclitaxel + Lapatinib (n=293)

Paclitaxel + Placebo (n=286)

Capecitabine + Lapatinib

Capecitabine

All grades 58% 26% 60% 39%

Grades 3-4 15-<1% 1-0% 12-1% 11-0%(a) (b)

(a) 3 deaths due to septic shock and diarhoea(b) management of side effects improved with

introduction of guideleines

Trastuzumab & Pertuzumab

KA Gelmon….PF Conte

Herceptin and pertuzumab bind to distinct epitopes on HER2 extracellular domain

Activates antibody-dependent cellular cytotoxicity

Inhibits HER2-mediated signalling

Inhibits shedding and, thus, formation of new p95

Inhibits HER2-related angiogenesis

Hubbard 2005

Herceptin

Pertuzumab

Activates antibody-dependent cellular cytotoxicity

Prevents receptor dimerisation

Potent inhibitor of HER2/HER2- and HER2/HER3-mediated signalling pathways

Tanespamycin + Trastuzumab

S Modi, MSKCC

Trastuzumab DM1

Scott Holden

Trastuzumab and RAD001

99

RAD001 (Everolimus) Inhibits Tumor Cell Growth and Angiogenesis

Cancer Cell Endothelial Cell

mTOR

PI3K

AKT/PKB

Reduced cell growth

and proliferation

Protein Production

Reduced gene

transcription

Reduced VEGFproduction

Reduced

cell growth

Reduced

proliferation

Nutrientsamino acids

Integrins

ILK

4E-BP1

eIF-4E P 70 S6k

Energy

PTEN

TSC1/2

mTOR

PI3K

AKT/PKB

FKBP12

RAD001

Growth factors

FKBP12

RAD001RAD001

VEGF

VEGFR

100

Efficacy

Three of the four Partial Responses assessable for biomarker expression were PTEN+ and four were pAKT473+

Best Overall Response

Overall(N=13)

5 mg Daily (N=5)

10 mg Daily (N=1)

30 mg Weekly (N=7)

Partial Response 6 /13 (46%)

4 0 2

Stable Disease 6 1 1 (7+) 4

Disease Control

(PR / SD>16 Weeks)

10/11

(91%)

5 NA 5

Progressive Disease 1 0 0 1

http://media.asco.org/player/player_mgmt.htm?click=yes&slide=20

103

Acetylated -tubulin

-tubulin

ERER

HER2HER2

HSP90

DAC Inhibition Decreases Cell Proliferation and Prevents Invasiveness of Breast Cancer cells

DAC Inhibition in Breast Cancer Cells

DAC DAC InhibitorInhibitorDAC DAC InhibitorInhibitor

HDAC6HDAC6

Microtubule depolymerization

Acetylated HSP90– binding to HER2/ER prevented

Stabilization

Motility and Invasion

Microtubules stabilized

Proliferationand Survival

HER2/ER degraded

• Efficacy at weeks 6 and 12 using RECIST• Continuing patients assessed q 12 weeks • Study treatment discontinued when disease progression or

other

ENROLLME NT

Patient Population

• Stage IIIb/IIIc/IV

• HER2+

• Pretreated or untreated with trastuzumab

Safety Analysis After 10 Pts • If ≤ 3 tox. events at w6

•Recruit up to 50 pts• If 4+ tox. events at w6

•Reduce lapatinib to 1000 mg QD

•Evaluate 10 more pts •If acceptable, recruit to 50 pts

•If not, terminate study

Study Design

Lapatinib

1500 mg QD

+

Bevacizumab 10 mg/kg

q2w

N = 10 50

H Rugo, ASCO 2008

Efficacy: 12-week PFS and Best Response

• Crude 12-week PFS rate was 62.5% (95% CI: 43.7, 78.9)• Clinical benefit rate was 34.4% (95% CI: 18.6, 53.2)

Patients, n (%)

Lap + bevn = 32

Complete response (CR) 0

Partial response (PR) 4 (13)

Stable disease (SD) at 12 weeks 14 (44)

Stable disease 24 weeks 7 (22)

Clinical benefit (CR + PR + SD 24 weeks) 11 (34)

Progressive disease 9 (28)

Unevaluable* 5 (16)

* 5 patients withdrew prior to radiologic assessment at week 6.

H Rugo, ASCO 2008

D Slamon ASCO 2008

Conclusions

Risk Ratio for DFS of ACTH vs ACT

FISH+ (1588)

FISH- (207)

IHC 3+ (1488)

IHC <3+ (299)

FISH-&IHC <3+ (174)

0.00 0.25 0.50 0.75 1.00 1.25 1.50

0.4 p<0.0001

0.40 p=0.026

0.48 p<0.0001

0.32 p=0.0017

0.34 p=0.014

RR P Value


Effects of lapatinib on BTCs. Modified from J Chang, Miami Breast Cancer Conference

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Targeting the HER2 network: what’s new? P Pronzato, Genova.

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